Kaposi's sarcoma (KS) is a vascular, proliferative disorder involving endothelial cells, fibroblasts, and characteristic spindle-shaped mesenchymal cells. Kaposi's sarcoma is epidermic among HIV infected individuals, and is a substantial cause of morbidity and mortality in this group(1,2). Cultures of diploid, non-immortalized spindle cells (KS cells, KSC) have been derived from pleural effusions and from explants of lesion biopsies of KS patients by a number of investigations(3-10). Autocrine pathways involving IL-6 and bFGF have been shown to be important for the proliferation of these cells(4,6,10). Oncostatin M, TNF alpha, and the HIV-1 tat protein (TAT), may also play important roles in KS cell proliferation and KS induced angiogenesis(11-13). Recent studies have indicated that all-trans retinoic acid (tretinoin, ATRA) is an effective topical agent for cutaneous KS(14). In preliminary experiments(5), ATRA was found to be capable of inhibiting the growth of KS cells at nanomolar to micromolar concentrations without altering expression of IL-6, bFGF, or their respective receptors, unlike the mechanism of action indicated by previous studies demonstrating that retinoid inhibition of melanoma growth and endothelial cell proliferation is mediated through reduction of IL-6 and/or bFGF receptor expression(15- 18). In preliminary studies, tretinoin was also found to be capable of inducing apoptosis in treated KS cells. This effect was accompanied by the induction of high levels of expression of fas, myc, and TNFR1 proteins, a novel effect of retinoids, suggesting the activation of pathways of programmed cell death similar to those shown to be involved in growth factor withdrawal of fas mediated apoptotic death of activated lymphocytes(19-21). The objectives of this study are to extend investigations into the nature of the action of retinoids on KS cells in two directions: [1] To determine the mechanism of retinoid mediated inhibition of KS cell proliferation, concentrating on the induction of differentiation in these target cells, by analyzing the effects of retinoid treatment on surface markers, defining the susceptibility of retinoid treated cells to the proliferative effects of TAT, and examining the effects of retinoids selective for specific nuclear receptor proteins, and [2] To determine the molecular basis of apoptosis induced by retinoid treatment in KS cells, clarifying the involvement of known pathways of apoptosis, including the involvement of fas, TNF alpha, bcl-2, bax, myc, max, p53, and the interleukin-1 converting enzyme (ICE), with emphasis upon identification of agents acting synergistically with retinoids to potentiate apoptotic killing (such as fas antibody or TNF alpha). The effects of TAT on retinoid induced apoptosis, and a systematic approach to identify growth factor(s) or receptors involved in retinoid induced apoptosis in KS cells will also be investigated.